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KMID : 0613820100200070969
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Journal of Life Science
2010 Volume.20 No. 7 p.969 ~ p.976
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Pharmacological Profile of KR-31125, an Orally Active AT₁ Receptor Antagonist
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Lee Sung-Hou
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Abstract
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In vivo studies of KR-31125 (2-butyl-5-dimethoxymethyl-6-phenyl-7-methyl-3-[[2"-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) were performed in pithed rats, conscious angiotensin II (AII) challenged normotensive rats, renal hypertensive rats (RHRs) and furosemide-treated beagle dogs. KR-31125 induced a non-parallel right shift in the dose-pressor response curve to AII (ID50: 0.095 ㎎/㎏) with a dose-dependent reduction in the maximum responses in pithed rats. Compared to losartan, this antagonistic effect was about 18 times more potent, presenting competitive antagonism. Other agonists such as norepinephrine and vasopressin did not alter the responses induced by KR-31125. Orally administered KR-31125 had no agonistic effect and dose-dependently inhibited the pressor response to AII with a slightly weaker potency (ID50: 0.25 and 0.47 ㎎/㎏, respectively) in the AII-challenged normotensive rat model, but with a more rapid onset of action than losartan (time to Emax: 30 min for KR-31125 and 6 hr for losartan). KR-31125 produced a dose-dependent antihypertensive effect with a higher potency than losartan in RHRs, and these effects were confirmed in furosemide-treated dogs where they presented a dose-dependent and long-lasting (>8 hr) antihypertensive effect with a rapid onset of action (time to Emax: 2-4 hr), as well as a 20-fold greater potency than losartan. These results suggest that KR-31125 is a potent, orally active AT₁ receptor antagonist that can be applied to the development of new diagnostic and research tools as an added exploratory potential of AT₁ receptor antagonist.
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KEYWORD
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KR-31125, angiotensin, AT₁ receptor antagonist, antihypertension, diagnostics
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